Faculty of Medicine, University of Toronto, Toronto, Canada
Hyperpigmentation disorders of the skin are common and can be the source of significant psychosocial distress for patients. The most common of these disorders are melasma and postinflammatory hyperpigmentation. Sunscreen use and minimizing sun exposure are crucial in all cases. Topical applications are the mainstay of treatment and include phenols, retinoids, corticosteroids, and their combinations.
hyperpigmentation, melasma, postinflammatory hyperpigmentation, PIH
Hyperpigmentation of the skin is a very common problem, with many patients seeking therapies to improve their cosmetic appearance. It is the result of an increase in cutaneous melanin deposition either by increased melanin synthesis or, less commonly, by a greater number of melanocytes. The amount of color change depends on the location of the melanin deposition. Epidermal involvement appears as brown discoloration whereas dermal deposition appears as blue-grey.1 Mixed epidermal and dermal depositions appear as brown-grey discolorations. The use of a Wood’s lamp can often be very beneficial in determining the location of melanin deposition showing enhancement of color contrast in lesional skin for the epidermal type, but not the dermal types. The mixed type has enhancement in some areas of lesional skin, but not in other areas.2 Whether the melanin is deposited in the epidermis or dermis is important therapeutically because dermal hyperpigmentation is much more challenging to treat.3
The most common pigmentation disorders for which patients seek treatment are melasma and postinflammatory hyperpigmentation (PIH). These conditions may have a major impact because disfiguring facial lesions can significantly affect a person’s psychological and social wellbeing, contributing to lower productivity, social functioning, and self-esteem.4,5
Melasma is a common acquired pigmentary disorder that occurs mainly in women (more than 90% of cases)6 of all racial and ethnic groups, but particularly affects those with Fitzpatrick skin types IV–VI.7 While the cause of melasma is unknown, factors include: a genetic predisposition, ultraviolet light exposure, and estrogen exposure.8 Estrogen is thought to induce melasma as it often develops during pregnancy, with use of oral contraceptives, and with hormone replacement therapy (HRT) in postmenopausal women.9 Melasma in pregnancy usually clears within a few months of delivery.
Discontinuation of oral contraceptives or HRT, in combination with adequate sun protection, may also result in melasma clearance,10 although there is a paucity of literature with regard to HRT and the clearance of this condition.
Melasma presents as brown to grey macules and patches, with serrated, irregular, and geographic borders.7 The pigmented patches are usually sharply demarcated10 and symmetrical. Melasma has a predilection for sun-exposed areas. The three major patterns of distribution are: centrofacial (cheeks, forehead, upper lip, nose, and chin) (66% of cases), malar (cheeks and nose) (20% of cases) and mandibular (rami of the mandible) (15% of cases). See Table 1 for the differential diagnosis.8
Postinflammatory Hyperpigmentation (PIH)
PIH represents a pathophysiologic response to cutaneous inflammation, such as acne, atopic dermatitis, lichen planus, and psoriasis. Similar to melasma, it is more obvious in patients with brown or black skin.8 It has no gender or age predominance.10 The lesions are characteristically limited to the site of the preceding inflammation and have indistinct, feathered borders.7 Melanocytes can either be stimulated by the inflammatory process to become hypertrophic, thus secreting more melanin, or the number of melanocytes can increase. Epidermal hyperpigmentation (e.g., associated with acne) occurs when increased melanin is transferred to keratinocytes while dermal pigmentation (e.g., associated with lichen planus and cutaneous lupus erythematosus) occurs when the basement membrane is disrupted and melanin falls into the dermis and resides within melanophages.8
|Cutaneous mercury deposits||• History of mercury containing soaps/creams|
• Dermatitis may be present
|Drug-induced hyperpigmentation||• History of medication|
• Hyperpigmentation less patterned and less irregular
|Erythema dyschromicum perstans||• Gray to blue-brown lesions|
• Inflammatory phase with rim of erythema occasionally seen
• Distribution includes nonsun-exposed areas
|Exogenous ochronosis||• History of hydroquinone application|
• Banana-shaped, yellow-brown deposits in the dermis
|Lichen planus actinicus||• Fine scale overlying violaceous lesions|
|Postinflammatory hyperpigmentation||• History or presence of inflammation with erythema, and/or scaling|
|Table 1: Differential Diagnosis of Melasma|
Any inflammatory disorder can be associated with PIH, including:
- Acne vulgaris
- Atopic dermatitis
- Discoid lupus erythematosus
- Erythema dyschromicum perstans
- Fixed drug eruption
- Generalized drug eruption
- Idiopathic eruptive macular pigmentation
- Insect bites
- Irritant and allergic contact and photocontact-
- Lichen planus
- Lichen simplex chronicus
- Pityriasis rosea
- Polymorphous light eruption
- Trauma (i.e., burns, abrasions, postsurgical)
- Viral exanthem
Therapeutic goals for hyperpigmentation include promoting the degradation of melanosomes, inhibiting the formation of melanosomes, and retarding the proliferation of melanocytes.11 Because sun exposure is an important etiologic factor in hyperpigmentation, all patients should use daily, broad-spectrum, high SPF sunscreens and minimize sun exposure.12 Although this practice is widely used there are no clinical trials to support its therapeutic benefit. Most of the therapies used for hyperpigmentation have been studied in melasma and the same treatment principles hold for PIH.3
Topical Treatments for Melasma
In those patients with epidermal type melasma, there are multiple treatments available (see Table 2).6 Topical agents include phenols, e.g., hydroquinone (HQ); retinoids, e.g., tretinoin; azelaic acid; kojic acid (KA); and glycolic acid (GA).
HQ 2%–4% has been widely used for melasma therapy. It inhibits the conversion of dopa to melanin by inhibiting the activity of tyrosinase.13 Moreover, Jimbow, et al. proposed that it may interfere with DNA and RNA synthesis, degrade melanosomes, and destroy melanocytes.14
There are rare case reports of allergic contact dermatitis to HQ,15-17 however, irritant reactions are more common, with up to 25% developing an itchy eruption as demonstrated in a recent randomized control trial.18 We recommend that patients test HQ on a hidden area, e.g., the upper inner arm, prior to use on areas that are especially visible, such as the face.
Ennes, et al. compared HQ 4% with placebo over 12 weeks in 48 patients who had melasma. Thirty-eight percent of HQ patients showed total improvement and 57% demonstrated partial improvement. Only 8% of placebo patients achieved total improvement and 17% were treatment failures.19 Side-effects included irritant and allergic contact dermatitis, PIH, nail bleaching and rarely, ochronosis-like pigmentation.8 Toxicity studies have shown HQ is capable of inducing renal adenoma in rats and is fetotoxic in animals.20 These findings influenced the EU to ban HQ agents as a cosmetic. However, these complications have not been reported in humans.21
Under no circumstances should monobenzylether, or any other ethers of HQ, be used to treat melasma as they can lead to a permanent loss of melanocytes with the development of a disfiguring confetti-like leukoderma.7
Tretinoin 0.05%–0.1% reduces pigmentation by inhibiting tyrosinase transcription, as well as by interrupting melanin synthesis.22 While tretinoin may be effective in reducing melasma, it typically takes at least 24 weeks to see clinical improvement.23 It may also increase pigmentation secondary to irritation10 and may cause erythema and peeling.24 Other retinoids including adapalene, tazarotene and topical isotretinoin have also been used.25,26
Azelaic acid (15%–20%) (Finacea®, Intendis), a C9 dicarboxylic acid, is a reversible inhibitor of tyrosinase27 and may also have both cytotoxic and antiproliferative effects on melanocytes.28 In a randomized, double-blind study, azelaic acid was shown to be as effective as HQ 4% but without its side effects.29 The combination of azelaic acid with 0.05% tretinoin or 15%–20% glycolic acid may produce earlier, more pronounced skin lightening.8 Adverse effects include pruritus, mild erythema, scaling, and burning.28
KA 2% is produced by the fungus Aspergilline oryzae and is a tyrosinase inhibitor.7 It is generally equivalent to other therapies but may be more irritating.30 In one double-blind study, KA 2% combined with HQ 2% was shown to be superior to glycolic acid (GA) 10% and HQ 2%.31 Another double-blind study compared GA 5% with either HQ 4% or KA 4% for 3 months. Both combinations proved equally effective with reduction of pigmentation in 51% of patients.32 KA may be effective if a patient has difficulty tolerating other first-line therapies.30
GA 5%–10% is an alpha-hydroxy acid and has been studied in combination with other agents. It decreases pigment by many mechanisms including thinning the stratum corneum, enhancing epidermolysis, dispersing melanin in the basal layer of the epidermis, and increasing collagen synthesis in the dermis.2 One combination study compared GA 10% plus HQ 4% in a cream that included vitamins C and E and sunscreen vs. sunscreen cream alone. Seventy-five percent of patients improved using the treatment enhanced cream compared with only 13% who used the sunscreen alone. Mild irritation was a common adverse effect.33
Combination therapy is more effective than single agents used alone. The etiology of melasma is not completely understood, thus, therapies that can act at different stages of pigmentation can produce better clinical results than a single therapy acting at a single stage.6
The addition of tretinoin eliminates pigment and increases keratinocyte proliferation by preventing the oxidation of HQ and improving epidermal penetration. Further, adding topical corticosteroids reduces the irritative effects of hypopigmenting agents, and inhibits melanin synthesis by decreasing cellular metabolism.6 This combination, HQ 5%, tretinoin 0.1%, and dexamethasone 0.1%, was first introduced in 1975 and termed the Kligman formula after its inventor. It has been the most extensively used combination therapy for melasma worldwide.34
More recently, results from a multicenter, randomized, double-blind control trial demonstrated that a new combination of HQ 4%, tretinoin 0.05%, and fluocinolone acetonide 0.01% (Tri-Luma®, Galderma) proved better than any combination of two of the above agents, with 77% of patients showing complete or nearly complete clearing. Clinically significant improvement was noted as early as 4 weeks with maximum results at 8 weeks. The most common adverse effects were mild local irritation, erythema, and skin peeling.35 The mixture should be applied to the entire affected area to avoid blotchiness. The recent 2006 consensus of the Pigmentary Disorders Academy (PDA), a group of international dermatologists and leaders in pigmentary disorders who receive sponsorship from Galderma, supported the use of triple therapy.
The PDA consensus suggested that first-line therapy for melasma should consist of fixed topical therapies and only when triple combination therapy is unavailable or patients have a sensitivity to the ingredients, should dual ingredients or single agents be considered.6
Over-the-counter (OTC) products are readily available, and many patients have already tried these measures prior to consulting a dermatologist. At the present time the available concentrations of HQ for OTC use are not as efficacious as prescription formulations.36 Alpha and beta hydroxy acid home chemical peels and topical vitamin A are also available.
The combination of N-acetyl glucosamine (NAG) and niacinamide (Olay® Definity®) was recently shown to reduce facial hyperpigmentation in Japanese and Caucasian subjects with facial hyperpigmentation in two double-blind, vehicle-controlled, split-face, left-right randomized clinical studies.37 In another double-blind, vehicle-controlled, full-face clinical study, a significant reduction in facial hyperpigmented spots was seen in patients with facial hyperpigmentation using the NAG 2% + niacinamide 4% formulation when compared with the vehicle regimen.38 There were no adverse effects reported.
Quality of Evidence*
|Epidermal||Topical||Phenols (e.g., HQ)||B-C|
|Retinoids (e.g., tretinoin)||B-C|
|Combination||HQ, retinoid, corticosteroid||A-B|
|KA & GA||B|
|HQ & GA||B|
|Chemical Peels||Alpha hydroxy acids (GA)||B-C|
|Dermal||Pulsed CO2 laser followed by Q-switched alexandrite laser||C|
|Table 2 : Melasma Therapies. Similar therapies are used clinically to treat PIH. Note: for all therapies sunscreen use and UV avoidance is important.|
*Quality of Evidence6
A There is good evidence to support the use of this procedure.
Other topical therapies have been used including ascorbic acid, licorice extract and, in the past, mercury.6
Treatment During Pregnancy
Treatment of melasma in pregnant women is routinely deferred until after delivery. This is because, first of all, melasma is more resistant to treatment because the hormonal trigger for it persists throughout pregnancy.39 Second, therapy may be unnecessary since most women have a significant improvement in melasma after parturition. Third, therapy for melasma is contraindicated during pregnancy.
Treatment of PIH
Initial treatments for PIH should, if possible, manage and control the underlying skin condition.10 To lower the risk of PIH in patients with inflammatory conditions such as acne and atopic dermatitis, they should present early to a physician. As with melasma, sunscreen and sun avoidance are extremely important. Other treatment options are similar to those discussed above for melasma.2 A clinical trial evaluated the effects of 0.1% tretinoin cream on PIH in patients with Type VI skin. Although significant lightening effects were seen, 50% of patients in the treatment group experienced moderate dermatitis.40
Another PIH treatment study observed the addition of GA peels to a topical regimen of HQ 2%, GA 10% and tretinoin 0.05% cream in PIH patients with Type VI skin. This study showed improvement with peels and minimal adverse effects.41 However, as mentioned earlier, caution must be taken when performing peels on darker skinned patients because there is a higher risk of hyperpigmentation.30
Hyperpigmentation, most commonly melasma and PIH, remain a therapeutic challenge. Multiple topical modalities can be used, and combination topical therapies are the current first-line approach.
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- Victor FC, Gelber J, Rao B. Melasma: a review. J Cutan Med Surg. 8(2):97-102 (2004 Mar-Apr).
- Cayce KA, Feldman SR, McMichael AJ. Hyperpigmenation: a review of common treatment options. J Drugs Dermatol 3(6):668-73 (2004 Nov-Dec).
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- Bolognia JL, Jorizzo JL, Rapini RP. Dermatology. Toronto: Mosby (2003).
- Johnston GA, Sviland L, McLelland J. Melasma of the arms associated with hormone replacement therapy. Br J Dermatol 139(5):932 (1998 Nov).
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- Pandya AG, Guevara IL. Disorders of hyperpigmentation. Dermatol Clin 18(1):91-8 (2000 Jan).
- Pathak MA, Fitzpatrick TB, Kraus EW. Usefulness of retinoic acid in the treatment of melasma. J Am Acad Dermatol 15(4 Pt 2):894-9 (1986 Oct).
- Palumbo A, d’Ischia M, Misuraca G, Prota G. Mechanism of inhibition of melanogenesis by hydroquinone. Biochem Biophys Acta 1073(1):85-90 (1991 Jan).
- Jimbow K, Obata H, Pathak MA, Fitzpatrick TB. Mechanism of depigmentation by hydroquinone. J Invest Dermatol 62(4):436-49 (1974 Apr).
- Barrientos N, Ortiz-Frutos J, Gomez E, Iglesias L. Allergic contact dermatitis from a bleaching cream. Am J Contact Derm 12(1):33-4 (2001 Mar).
- Romaguera C, Grimalt F. Dermatitis from PABA and hydroquinone. Contact Dermatitis 9(3):226 (1983 May).
- Camarasa JG, Serra-Baldrich E. Exogenous ochronosis with allergic contact dermatitis from hydroquinone. Contact Dermatitis 31(1):57-8 (1994 Jul).
- Haddad AL, Matos LF, Brunstein F, Ferreira LM, Silva A, Costa D Jr. A clinical, prospective, randomized, double-blind trial comparing skin whitening complex with hydroquinone vs. placebo in the treatment of melasma. Int J Dermatol 42(2):153-6 (2003 Feb).
- Ennes SB, Paschoalick RC, Mota De Avelar Alchorne M. A double-blind, comparative, placebo-controlled study of the efficacy and tolerability of 4% hydroquinone as a depigmenting agent in melasma. J Dermatolog Treat 11(3):173-9 (2000 Sep).
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- Mahé A, Ly F, Perret JL. Systemic complications of the cosmetic use of skin-bleaching products. Int J Dermatol 44(Suppl 1):37-8 (2005 Oct).
- Romero C, Aberdam E, Larnier C, Ortonne JP. Retinoic acid as modulator of UVB-induced melanocyte differentiation. Involvement of the melanogenic enzymes expression. J Cell Sci 107(Pt4):1095-103 (1994 Apr).
- Griffiths CE, Finkel LJ, Ditre CM, Hamilton TA, Ellis CN, Voorhees JJ. Topical tretinoin (retinoic acid) improves melasma. A vehicle-controlled, clinical trial. Br J Dermatol 129(4):415-21 (1993 Oct).
- Grimes PE. Melasma. Etiologic and therapeutic considerations. Arch Dermatol 131(12):1453-7 (1995 Dec).
- Shroot B. Pharmacodynamics and pharmacokinetics of topical adapalene. J Am Acad Dermatol 39(2 Pt 3):S17-24 (1998 Aug).
- Leenutaphong V, Nettakul A, Rattanasuwon P. Topical isotretinoin for melasma in Thai patients: a vehicle-controlled clinical trial. J Med Assoc Thai 82(9):868-75 (1999 Sep).
- Nazzaro-Porro M. Azelaic acid. J Am Acad Dermatol 17(6):1033-41 (1987 Dec).
- Fitton A, Goa KL. Azelaic acid. A review of its pharmacological properties and therapeutic efficacy in acne and hyperpigmentary skin disorders. Drugs 41(5):780-98 (1991 May).
- Balina LM, Graupe K. The treatment of melasma. 20% azelaic acid versus 4% hydroquinone cream. Int J Dermatol 30(12):893-5 (1991 Dec).
- Cayce KA, McMichael AJ, Feldman SR. Hyperpigmentation: An overview of the common afflictions. Dermatol Nurs 16(5):401-6, 413-16 (2004 Oct).
- Lim JT. Treatment of melasma using kojic acid in a gel containing hydroquinone and glycolic acid. Dermatol Surg 25(4):282-4 (1999 Apr).
- Garcia A, Fulton JE Jr. The combination of glycolic acid and hydroquinone or kojic acid for the treatment of melasma and related conditions. Dermatol Surg 22(5):443-7 (1996 May).
- Guevara IL, Pandya AG. Safety and efficacy of 4% hydroquinone combined with 10% glycolic acid, antioxidants, and sunscreen in the treatment of melasma. Int J Dermatol 42(12):966-72 (2003 Dec).
- Kligman AM, Willis I. A new formula for depigmenting human skin. Arch Dermatol 111(1):40-8 (1975 Jan).
- Taylor SC, Torok H, Jones T, et al. Efficacy and safety of a new triple-combination agent for the treatment of facial melasma. Cutis 72(1):67-72 (2003 Jul).
- Halder RM, Richards GM. Topical agents used in the management of hyperpigmentation. Skin Therapy Lett 9(6):1-3 (2004 Jun-Jul).
- Bissett D, Robinson LR, Li J, et al. Topical N-acetyl glucosamine reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster #236.
- Kimball AB, Bissett DL, Robinson LR, et al. Topical formulation containing N-acetyl glucosamine and niacinamide reduces the appearance of hyperpigmented spots on human facial skin. Presented at: the 64th Annual Meeting of the American Academy of Dermatology, San Francisco, CA; March 3-7, 2006. Poster #235.
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- Bulengo-Ransby SM, Griffiths CE, Kimbrough-Green CK, et al. Topical tretinoin (retinoic acid) therapy for hyperpigmented lesions caused by inflammation of the skin in black patients. N Engl J Med 328(20):1438-43 (1993 May).
- Burns RL, Prevost-Blank PL, Lawry MA, Lawry TB, Faria DT, Fivenson DP. Glycolic acid peels for postinflammatory hyperpigmentation in black patients. A comparative study. Dermatol Surg 23(3):171-4 (1997 Mar).